Targeting the PI3K/AKT/mTOR/NFkB Axis in Ovarian Cancer

Abstract

Phosphoinositol 3 Kinase (PI3K)Phosphoinositol 3 kinase (PI3K) defines a class of lipid kinases that have the ability to phosphorylate the inositol ring 3′-OH group in inositol phospholipids and therefore produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3) [1]. PI3K encompasses a family of enzymes divided into: Class IA PI3K which includes three isomers (α, β, δ) and Class IB which include the group (γ) [2,3]. PI3K Class IA is comprised of a regulatory subunit p85 along with a catalytic p110α subunit [4]. Mutations in the gene encoding the catalytic subunit of PI3K p110α, PIK3CA, are found in nearly 33% of clear-cell carcinoma cases [5,6], 20% of endometrioid and clear-cell carcinomas [7], 18-28% of cases of serous cystadenocarcinoma, with enhancement of the signature of activated PI3K in the majority of ovarian cancer cases irrespective of the subtype [8]. PIK3CA mutations are considered driver mutations that provide transformative advantages for high grade serous cancer (HGSC) [9]. Multivariate survival analysis revealed that PI3K protein expression was associated with poor survival in advanced HGSC [10]. In addition, several studies have shown that the rate of mutations in the PI3K pathway, especially in AKT and p70S6K, including missense mutations and amplifications, is correlated with higher rates of chemoresistance [11,12]. Chemo-sensitization could be achieved via downregulation of PI3K and/or its downstream effectors, . The increased activation of PI3K in OvCa and its role as a hub for several cancerpromoting pathways, explain its many implications in cancer progression including oncogenic transformation,

MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study

“…The selected 9 miRNAs resulted involved in the main biological processes which are hallmarks in the pathogenesis of OC. In particular, the predicted targets of the T/N-downregulated 7 miRNAs set were oncogenic pathways such as EMT, AKT, mTOR, ATF2, which have been implicated in various aspects of OC pathogenesis, diagnosis and treatment [ 50 – 52 ]. The most relevant target of the 2 T/N-upregulated miRNAs resulted the cell cycle regulation and MAPK/ERK pathway, which has been targeted by novel therapeutical agents seeking to overcome cisplatin resistance in OC [ 53 ].…”

“…The core network was built by using gene interactions of validated targets, and a second supportive network was constructed on the basis of protein-protein interactions using targets restricted also by target prediction and T/N-deregulation. Results were extensively overlapping, and most affected pathways resulted MTOR, AKT, MAPK, P53, and Wnt signaling pathways, shown to be pivotal in OC biology [ 50 , 51 , 53 – 55 ].…”

Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways

“…Based on previous literature, we have presented a summarized figure where we have shown the common and two well-studied signaling pathways for the insulin and insulin receptor and IGF-1 and IGF-1 receptor as well as for both cancer and diabetes (53)(54)(55)(56)(57). As in Figure 4, we see that PI3K-Akt and MAPK pathways are downstream to IGFR, so we may link the IGFR expression and genetic changes directly to cancer because these pathways are well-studied for cancer.…”

“…AKT-PI3K pathway is a thoroughly studied pathway in case of cancer, and there are a number of targets from this PI3K-AKT pathway (known to drive neoplastic behavior) for which drugs are available (55,(82)(83)(84)(85)(86). It is known that insulin receptors' family members are considered as the key activators for the PI3K-AKT pathway and are frequently activated by oncogenic episodes (mutations, loss of function, change in gene expression pattern) and few examples are overexpression of HER2, loss of PTEN function, and abnormal mutations in PI3K (2,78,(87)(88)(89)(90).…”

Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

“…Besides sterol, cancer cells develop multiple pro-tumorigenic signaling molecules and redundant molecular pathways to control SREBP expression and maintain the stability of mature nSREBP, thereby guaranteeing production of sufficient lipids for rapid cell growth and proliferation [ 140 ]. For example the PI3K/Akt/mTORC oncogenic signaling pathway, frequently activated in various cancers including ovarian cancer, plays a pivotal role in processing of SREBPs and regulating DNL [ 141 , 142 , 143 , 144 ]. Activation of receptor tyrosine kinases (RTKs) through growth factor binding recruits phosphatidylinositol-3-kinase (PI3K) to the plasma membrane, where it phosphorylates inositol-containing membrane lipids like phosphatidylinositol bisphosphate (PIP 2 ), generating the active form phosphatidylinositol trisphosphate (PIP 3 ).…”